Summary A progressive neurodegenerative condition that accounts for the majority of dementia cases in the elderly, Alzheimer's disease (AD) is already the sixth-leading cause of death in the US and is set to double in prevalence within the next decade. Neuropsychiatric symptoms (NPS), such as agitation, apathy, psychosis are core features of AD that are known to present commonly in prodromal phases of the disease, as well as in the advanced phase (Dementia). Despite decades of research, the underlying pathogenic mechanisms that lead to AD-associated NPS are poorly understood, although several hypotheses have been proposed, reflecting the heterogeneity of NPS across individuals. This application takes a precision medicine approach and focuses on the hypothesis that disruption of brain monoamine circuits is one of the causes of NPS emergence, in some individuals with NPS. This variability might for some patients reflect person-to-person differences in the activity/efficiency of their monoamine brain systems. This application is further based upon recent successes in our laboratory generating human induced pluripotent stem cells (hiPSCs) from patients with AD, as well as from healthy individuals, and differentiating them into human brain cells with amyloidogenic properties. Our overarching hypothesis is that person-specific iPSCs generated from the peripheral blood of 40 individuals total including (1) AD patients with NPS and (2) AD patients without NPS and differentiated into NPS relevant brain cells like serotonergic neurons?proposed here, will be useful in vitro models of mechanisms at the personal level. Further comparative studies of inter- individual variability in the physiologic functioning (neurotransmitter production, transcriptome) of these neurons could explain some cases/types of NPS, and predict utility of pharmacological therapies, such as serotonin reuptake inhibitors. We envision that this research will lay the groundwork for a new generation of in vitro human models of NPS, as well as for simple, easily reproducible predictive drug screening models in which the effectiveness of existing and new tailored therapeutic compounds can be tested.